Steroids and process for making same



Unite States Patent STEROIDS AND PROCESS FOR MAKING SAME TadeusReichstein, Weissensteinstrasse 22, Basel, Switzerland; Stefan AntoniSzpilfogel, Prinses Beatrixlaan 10, Oss, Netherlands; and David AdriaanVan Dorp, Hertogm Johannasingel 17, Oss, Netherlands No Drawing. FiledJan. 27, 1958, Ser. No. 711,163

Claims priority, application Switzerland Feb. 18, 1954 '3 Claims. (Cl.260-3403) This is a continuation-in-part application of our patentapplication Serial No. 488,426, filed February 15, 1955 (now abandoned).

This invention provides a new D-homo-androstene compound, andderivatives thereof, as well as process for manufacturing same. Moreparticularly this invention relates to the lactone of the 11-11p-hydroxy-17-formyl- D-homo-androstadiene-Zi-one-18-acid of theformula:

and the functional derivatives thereof. Functional derivatives arethose, which are formed with aldehydic and ketonic reagents, and arereadily convertible into the compound of the above formula; moreparticularly acetals, ketals, e.g. ethylenedioxy derivatives,mercaptals, thioketals, enol derivatives, such as enol esters, enolethers or enamines, hydrazones, semicarbazones, thiosemicarbazones, orthe like.

The lactone of the A -11p-hydroxy-17-forrnyl-D-homoandrostadiene-3-one-18-acid, or the functional derivatives thereofare key intermediates in the preparation of therapeutically valuablecompounds containing a formyl group in the 13-portion, such asaldosterone or the 17ot-hydroxylated derivative thereof, which isdescribed in our copending application, Serial No. 711,164 concurrentlyfiled herewith.

The new D-homo-androstene of the invention, or functional derivativesthereof may be converted into aldosterone according to the followingprocedure: After the D-homo-androstene compound has been converted intothe 3-ethylenedioxy derivative thereof, in which the double bond in the4-position is shifted into the 5-position, is, upon treatment of this3-ethylenedioxy derivative of the lactone of A-llfi-hydroxy-l7-formyl-D-homo-androstadiene-3-one-l8-acid with sodiumboron hydride, and esterification with benzoyl chloride, the benzoate.of the lactone of this compound is formed, which is further subjectedto treatment with lithium aluminium hydride and esterification withbenzoyl chloride. The thus ob tained dibenzoate of the113,18-cyc1osemiacetal of A llfi-hydroxy 17 hydroxymethyl 18 oxo 3ethylenedioxy D homo androstadiene is oxidized first with osmiumtetroxide and then with periodic acid to the dibenzoate of the218,4,3-cyclosemiacetal of 4bfi-methyl- 1p formylmethyl 25 formyl-2a(3hydroxy 2' oxopropyl) 7 ethylenedioxy 1,2,3,4,4aa,4b,5,6,7,8,10,lOaa-dodecahydrophenanthrene-4B-ol. The formation of the latter may alsobe accomplished by treatment of the dibenzoate of the115,18-cyclosemiacetal of A -IIp-hydroxy- 17 -hydroxymethyl-l8-oxo-3-ethylenedioxy-D-homoice androstadiene with ozone, then with zincin acetic acid! The ring closure to the dibenzoate of the1:1fi,18-cyclosem1- acetal of A-11,6,2l-dihydroxy-l8,20-dioxo-3-ethylenedioxy-pregnadiene may beaccomplished by treatment with piperidine in glacial acetic acid.Hydrogenation in the presence of a palladium-carbon catalyst removes thedouble bond in the l6-position and upon treatment with p-toluenesulfonic acid in acetone and, subsequently, with aquous potassiumhydrogen carbonate, the M-llaZI-dihydroxy-3,18,20-tri0xo-pregnene oraldosterone is formed.

The A 11B,17oc,21 trihydroxy 3,18,20 trioxo-preg-, nene may be preparedaccording to the process described in our copending application, SerialNo. 711,164, filed concurrently herewith, for example by treating thedibenzoate of the 11,8,18-cyclosemiacetal of A -115,21: dihydroxy 18,20dioxo 3 ethylenedioxy pregnadiene, referred to above, withhydrogenperoxide, splitting the 16,17a-epoxide ring with hydrogen bromide and removing the bromo atom in the 16-position by treatment with Raney nickel.The thus obtained dibenzoate of the 11,6,18-cyclosemiacetal of- A-11fl,17a,21-trihydroxy- 18,20-dioxo-3-ethylenedioxy-pregnene yields thedesired carbonate.

A 11p,17a,21 trihydroxy 3,18,20 trioxo pregnene by treatment withp-toluene sulfonic acid and, subse: quently, with an aqueous solutionofpotassium hydrogen The pregnene derivative thus obtained shows mineralcorticoid properties.

The new lactone of A -11fl-hydroxy-l7-formyl-D-homoandrostadiene-3-one-18acid of this invention, or derivatives thereofmay be prepared by treating the lactone of 4b? methyl 2B carboxy lfiformyl methyl 20a- (3' oxo propyl) 1,2,3,4,4aa,4b,5,6,7,9,10,10afidodecahydrophenanthrene-4B-ol-7-one or a functional deriva-v tivethereof with ring closing reagent,-and, if desired, converting anyres11lting,-functional derivative into the lactone of A-llB-hydroxy-l7formyl-D-homo-andror stadiene-S-one-lS-acid, and/or, ifdesired, converting the resulting lactone of A-1lfi-hydroxy-17-formyl-D-homoandrostadiene-Zl-one-l8-acid into afunctional derivative.

Functional derivatives of the starting material are more especiallyacetals or ketals, such as the 7-ethylenedioxy derivative, in which thedouble bond in the 8-position is shifted into the 8a-position. 1

A reagent suitable for bringing about the closure of the ring, isparticularly a mixture of piperidine with acetic acid.

The process of the invention may be carried out with racemates oroptically active compounds. The racemates may be separated into theirantipodes by methods, in themselves known, e.g. by chemical ormicro-biological methods.

The lactone of 4bfi-methyl-2fl-carboxy-lfi-formyl: methyl 2a (3 oxopropyl) l,2,3,4,4aa,4b,5,6,7,9,l0,loafi-dodecahydrophenanthrene-4fl-ol-7-one or a functional derivativethereof used as the starting material in the above reaction may beprepared according to the following procedure:4b[3-methyl-2-hydroxymethylene-7: ethylenedioxy1,2,3,4,4,aa,4b,5,6,7,8,10,l0a18 dodecahy drophenanthrenetp-ol-l-one,when condensed with acrolein, yields the 4bB-methyl-23-formy1-2a-(3'-oxo-propyl)- 7 ethylenedioxy1,2,3,4,4aa,4b,5,6,7,8,10,10au dodeca: hydrophenanthrene-4B-o1-l-onc,which is converted into its 3,3'-dimethoxy-propylacetal by treatmentwith metha 1101 in the presence ofhydrogen chloride. Uponoxida; tionwith a chromium trioxide-pyridine complex, the 25,4;8-1actone of4bfi-methyl-2fi-carbon-2a-(3',3-dimeth: oxy propyl) 7 ethylenedioxy1,2,3,4,4aa,4b,5,6,7,8, l0,10ap-dodecahydrophenanthrene-4fi-ol-l-one isformed,

which is reacted with lithium ethoxy-acetylene. The I4aa,4b,5,6,7,8,10,10a;8 dodecahydrophenanthrene 1,4}3- diol formed ishydrogenated in the presence of a palladium catalyst and rearranged bydehydration with a solution of thionyl chloride in pyridine to thelactone of 4bfi methyl 2e carboxy 1,1 'formyl methylene- 2oz (3',3'dimethoxypropyl) 7 ethylenedioxy' 1,2,3, 4,4aa,4b,5,6,7,8,l0,la,8 7dodecahydrophenanthrene 4/9- 01. Treatment with catalytically activatedhydrogen and splitting of the acetal with hydrogen chloride in thepresence of acetone yields the lactone of 4bB-methyl-2flcarboxy 1,3formyl methyl 2oz (3'-oxo propyl)- 7 ethylenedioxy1,2,3,4,4aa,4b,5,6,7,8,10,10afi dodecahydrophenanthrene-4B-o1, which byreatment with ptoluene sulfonic acid in acetone may be converted intothe lactone of 4be methyl-2p-carboxy-lp formylmethyl- 2m (3' oxo propyl)l,2,3,4,4aa,4b,5;6,7,9,10,10afidodecahydrophenanthrene-4 8-7-one. Thestarting material may also be used in the crude formwithout previouspurification. Thus, by'treating, for example, the lactone of 4b 3 methyl2/3 -'carboxy 1B formyl-methyl 2oz- 3,3' dimethoxy propyl) 7ethylenedioxy 1,2,3,4, 4aa,4b,5,6,7,8,10,10ap -dodecahydrophenanthrene4p 01 with an acetal splitting reagent, such as a hydrohalic acid, e.g.hydrogen chloride in acetone, the free aldehyde is obtained and is usedwithout any further purification in the ring closure step.

The following examples illustrate the invention; the relationship ofparts by'weight to parts 'by volume being the same as'that of the gramto the cubic centimeter.

Example 5 parts of the 'lactone of 4bB-methyl-2B-carboxy-1,3- formylmethyl 20c (3',3' dimethoxy propyl) 7- ethylenedioxyl,2,3,4,4aa,4b,5,6,7,8,10,10a/3 dodecahydrophenanthrene-4B-ol aredissolved in 250 parts by volume of dry acetone, and, after addition of1.65 parts by volume of hydrochloric acid of 36 percent strength,stirred for 3 minutes at room temperature. The mixture is neutralized bythe addition of 30 parts by volume of a l-molar aqueous sodium hydrogencarbonate solution, diluted with 2500 parts by volume of water, andthoroughly extracted with a mixture of methylene chloride and ether(1:3). The organic layer is washed with water, dried with'sodiumsulfate, filtered and evaporated in vacuo to dryness. The oily residue,which isthe crude lactone of 4b,? methyl 2,3 carboxy 1B -formylmethyl2o: (3- oxo-propyl) 7 ethylenedioxy 1,2, 3,4,4'aa,4b,5,6,7,'8,10,10apdodecahydrophenanthrene- 4,6 0], is dissolved in 450 parts by volume ofbenzene, mixed with 12 parts by volume of glacial acetic acid and 9parts by volume of piperidine, and boiled for 1 /2 hours in anatmosphere of nitrogen in an apparatus provided with a water-separator.After cooling, the solution is washed with Water, sodium hydrogencarbonate, and water, dried with sodium sulfate, and evaporated underreduced pressure. The residue is dissolved in benzene, andchromatographed over 150 parts of alumina. The combined benzene eluatesyield the lactone of the d,l- A 11 9 hydroxy 3 ethylenedioxy 17 formyl-D-homo-androstadiene-l8-acid, which is recrystallized from a mixture ofether, and petroleum ether.

Upon treatment of 1 part of the above ketal with a solution of 0.2 partby weight of p-toluene sulfonic acid in 60 parts by volume of acetonefor 12 hours at room temperature, and extraction of the reactionsolution, after addition of a saturated solution of sodium chloride,with chloroform, the desired d,l-A -11B-hydroxy-17-formyl-D-homo-androstadiene-3-one-18 acid may be obtained.

The lactone of 4b 8-methyl-Zp-carboxy lfiformylmethyl 2oz (3,3'dimethoxy propyl) 7 ethylenedioxy l,2,3,4,4aa,4b,5,6,7,'8,10,10a/3dodecahydrophe'nanthrene-4fl-ol used as the starting material, maybeprepared as follows:

A suspension of 100 parts of 4b 3-methyl-2-hydroxymethylene 7ethylenedioxy 1,2,3,'4,4au,4b,5,6,7,8,10,

4 10afl-dodecahydrophenanthrene-4fi-ol-1-one in 300 parts by volume ofdioxane is mixed at room temperature with 75 parts by volume of freshlydistilled acrolein, to which 0.125 part of hydroquinone has been added.The reaction mixture is stirred for 7 hours at room temperature, thewhole being dissolved, and the solution is allowed to stand for another16 hours. A solution of anhydrous methanolic hydrochloric acid of 1percent strength is cautiously added dropwise while cooling with ice andstirring, until the reaction mixture has a pH value of 7.0.

750 parts by volume of methanol are then added, the mixture is stirredfor 2 hours with cooling, the crystalline precipitate is filtered off,and washed on the filter with cold methanol. In this manner there areobtained 35 parts of 4bfl methyl 2/8 formyl 2a (3' 0x0- propyl) 7ethylenedioxy 1,2,3,4,4aa,4b,5,6,7,8,10, 10afidodecahydrophenanthrene-4/3-ol1-one melting at -177 C., which can befurtherpurified by recrystallization from benzene. The analytically pureproduct melts at 181 C.

.A suspension of 20.5 parts of 4bB-methyl-2B-formyl- 2a (3 oxo propyl) 7ethylenedioxy 1,2,3,4,4aa, 4b,5,6,7,8,l0,l0a;3 dodecahydrophenanthrene4/9 oll-one in 355 parts by volume of absolute methanol is gently heatedon the water-bath with the exclusion of moisture, a clear solution beingformed. The solution is cooled to 0 C. and 16.3 parts by volume of asolution of hydrochloric acid gas in absolute methanol containing 0.001part of hydrochloric acid per part by volume, is added while stirring.The reaction mixture is stirred for half an hour at a temperature of 0to +3 C., a crystalline precipitate slowly forming. The mixture isneutralized with a dilute solution of sodium methoxide in absolutemethanol, the mixture is suction-filtered, and the crystals are Washedwith cold methanol. By recrystallization from methanol or from a mixtureof benzene and methanol there is obtained thepure 4bfi-methyl- 2B formyl2a (3',3' -.dimethoxy propyl) 7 ethylenedioxyl,2,3,4,4a:z,4b,5,6,7,8,l0,10a,B dodecahydrophenanthrene-4 3-ol-1-onemelting at 188 C.

3.5 parts of 4bfi-methyl-2'B-formyl-2u-(3,3-dimethoxypropyl)- 7ethylenedioxy l,2,3,4,4aa,4b,5,6,7,8,10,lOafi-dodecahydrophenanthrene-4,6=ol-1one are dissolved in 2 parts byvolume of dry pyridine and mixed at room temperature and with stirringwith a chromium trioxidepyridine complex prepared from 3.5 parts ofchromium trioxide and 10 parts by volume of dry pyridine. The suspensionis stirred for 16 hours at room temperature, diluted with 50 parts byvolume of benzene, the benzene solution is washed several times "withwater and finally dried over sodium sulfate and evaporated to dryness invacuo. The residue 'is recrystallized from methanol. There is obtainedthe lactone of 4bp-methyl-2fl-carboxy- 2a (3,3 dimethoxy propyl) 7ethylenedioxy- 1,2,3,4,4au,4b,5,6,7,8,10,10afldodecahydrophenanthrene-4fi-ol-1-one in colorless crystals which meltafter recrystallization from methanol at 182 C. and in the infraredspectrum show an absorption band at 5.59 1. characteristic of a -lactonegroup.

To 3.47 parts of clean lithium Wire covered with 200 parts by volume ofether there areadded slowly dropwise with stirring in a dry atmosphereof nitrogen 26.25 parts by volume of freshly distilled bromobenzene. Thereaction occurs With gentle boiling. As soon as all the bromobenzene hasbeen added, the reaction mixture is boiled under reflux gently for 1 /2hours, the lithium being completely consumed. The mixture is cooled to0C. and slowly mixed with "a solution of 19.25 parts of freshly preparedethoxy-acetylene in 60 parts by volume of absolute benzene free fromthiophene. Thereupon the lithium-ethoxy-acetylene compound precipitatesin the form of a White precipitate. The reaction mixture isslowly-heated to room temperature and mixed with a=solution-of 10l5parts of the lactone of4b13-methylam ss 2B carboxy 2v. (3',3 dimethoxypropyl) 7 ethylenedioxy- 1,2,3,4,4aa,4b,5,6,7,8,10,10a,8--dodecahydrophenanthrene-4fl-ol-1-one in 100 parts by volume of'drybenzene free from thiophene. The reaction mixture is stirred for 2 hoursat room temperature under nitrogen, then'poured on to 1000 parts of icewater, thoroughly shaken and the aqueous phase extracted three timeswith 750 parts by volume of a mixture of benzene and ether (1:1) eachtime. The combined organic phases are washed with water until thereaction is neutral to litmus, dried with sodium sulfate, filtered andevaporated to dryness in vacuo. The oily residue is dissolvedin 45 partsby volume of ether. After being allowed to stand some time at roomtemperature crystals begin to'precipitate. After standing for 16 hoursat 6 C. crystallization is complete. The crystalline precipitate isfiltered with suction and washed on the filter with a mixture ofpetroleum ether and'ether (1:1). After recrystallization from etherthere is obtained the pure lactone of 4bfi-methyl-2flcarboxy 113 ethoxy-ethinyl 2m (3,3 dimethoxypropyl) 7 ethylenedioxy1,2,3,4,4aa,4b,5,6,7,8,10, 10a 8 dodecahydrophenanthrene 104,413 diolmelting at 156-157 C. From the mother-liquor there is obtained bychromatography over alumina and elution with a petroleum ether ethermixture 1:1, thelactone of 4b}?- methyl 2B carboxy 1oz ethoxy ethinyl20c (3,3- dimethoxy propyl) 7 ethylene dioxy 1,2,3,4,4aa,4b,5,6,7,8,10,l0a;3 dodecahydrophenanthrene 15,45- diol, which oncrystallisation from ether gives the'pure compound melting at 143 144 C.

A solution of 5 parts of the lactone of 4bp-methyl-2ficarboxy lfl ethoxyethinyl 2m (3',3 dimethoxypropyl) 7 ethylenedioxy1,2,3,4,4aa,4b,5,6,7,8,10, 1OaB-dodecahydrophenanthrene-lMAB-diol in 250parts by volume of alcohol and 0.5 part by volume of pure pyridine isagitated in the presence of 0.25 part of a palladium calcium carbonatecatalyst of 10 percent strength in an atmosphere of hydrogen at roomtemperature. After one molecular equivalent of hydrogen has been takenup, the reaction ceases. The mixture is filtered from the catalyst,through a thin layer of Super Cel, the filter is washed with alcohol,and the filtrate is evaporated to dryness under reduced pressure. Thecrystalline residue is recrystallized from a mixture of ethyl acetateand petroleum ether. The resulting lactone of 4b1S-methyl-2B- carboxy1;? ethoxy vinyl 20c (P/,3 dimethoxypropyl) 7 ethylenedioxy1,2,3,4,4au,4b,5,6,7,8,10, 10a,8 dodecahydrophenanthrene 111,4 3 diolmelts at 184-186 C.

A solution of 3.3 parts of the lactone of 4b,8-methyl- 25 carboxy 1Bethoxy vinyl 2a (3,3' dimethoxy propyl) 7 ethylenedioxy1,2,3,4,4aa,4b,5,6,7,8, 10,10a/8 dodecahydrophenanthrene 10:,45 diol in135 parts by volume of anhydrous pyridine is mixed with .38 parts byvolume of a 2-molar solution of purest thionyl chloride in anhydrouspyridine at C. in an atmosphere of nitrogen in the course of 2 minutes.After stirring for 15 minutes at 0 C. the reaction mixture is poured onto 700 parts by volume of a cold 0.5-molar solution of sodium hydrogencarbonate and washed with 1000 parts by volume of methylene chloride.The .mixture is thoroughly agitated and the organic layer is washed withicecold 0.5-molar sodium hydrogen carbonate solution and with coldwater, dried with sodium sulfate, and after filtration'the solution isevaporated .to dryness under reduced pressure. By crystallizing theresidue from ether there is obtained the lactone of4bfi-methyl-2fi-carboxy- 1,1 formyl methylene 2a (3',3' dimethoxypropyl) 7 ethylenedioxy1,2,3,4aa,4b,5,6,7,8,10,10afidodecahydrophenanthrene-4B-ol melting at206 -207 C. which in the ultra-violet spectrum shows an absorptionmaximum at 236 mu (log=3.85).

3.75 parts of this lactone are dissolved in 100 parts by volume ofalcohol and inithe presence of 1.1 parts of a palladium barium sulfatecatalyst of percent strength agitated at room temperature in anatmosphere. of hydrogen. ,After 0.97 molecular equivalent of hydrogenhas been taken up the reaction is interrupted. The mixture is filteredoff from the catalyst and the filtrate is .evaporated in,vacuo. From theresidue there is obtained by crystallization from a mixturerof etherand, petroleum ether the lactone of4bfl-methyl-2B-carboxy-1,8-formylmethyl 2a (3",3', dimethoxy-propyl).7.- ethylenedioxy .1,2,3,4,4a0! ,4b,5,6,7,8,10,10313,-dodecahydrophenanthrene-4B-ol, meltingat 188189 C. I

The lactone of the d,l-A -l1fihydroxy-l7-formyl D-homo-androstadiene-3-one-l8-acid of this invention or a functionalderivative. thereof may be converted into ,aldosterone according to thefollowing method: A solution of 6.2 parts of the lactone of d,l-A-'llB-hydroxy-Ii-ethylenedioxy 17 -,formy1 D homo androstadiene 18- acidin 200 parts by volume of alcohol is stirred for 16. hours at roomtemperature after the addition of 0.8 part of sodium boron hydride. Bythe cautious addition of 2 parts by volume of glacial acetic acid theexcess of the reducing agent is destroyed, the mixture is diluted with2000 parts by volume of water and extracted 3 times with 250 parts byvolume of methylene chloride each time. The methylene chloride solutionis washed with water, dried with sodium sulfate, filtered andevaporated. The dry residue is dissolved in 24 parts by volume ofanhydrous pyridine and slowly mixed with 2.9 parts by volume of freshlydistilled benzoyl chloride at 5 C. withstirring and the exclusion ofmoisture, care being taken that the temperature does not rise above 7 C.Stirring is continued for a half an hour at 5 C. and then thetemperature is allowed to rise slowly to room temperature. After 16hours the mixture is poured on to 340 parts by volume of ice water andwashed with 100 parts by volume of methylene chloride. The mixture isextracted twice more with 150 parts by volume of methylene chloride eachtime, the extracts are washed with cold l-molar sodium hydrogencarbonate solution, water, dilute hydrochloric acid and again withWater, dried with sodium sulfate and evaporated in vacuo. The residue isdissolved in 20 parts by volume of benzene and after a short treatmentwith active charcoal is filtered through a small column of alumina. Fromthe filtrate there is obtained after concentration and mixing withpetroleum ether the benzoate of lactone of d,l-A -llfi-hydroxy-3ethylenedi oxy 17 hydroxymethyl D homo androstadiene-18- acid which ispurified by crystallization from a mixture of acetone and water. I

To a solution of 4.9 parts of the benzoate of lactone of d,l-A 11,8hydroxy 3 ethylenedioxy 17 hydroxymethyl D homo androstadiene 18 acid in27 parts by volume of tetrahydrofurane is added dropwise a solution of0.21 part of lithium aluminum hydride in tetrahydrofurane at 15 C. withstirring. During this operation the temperature is kept below 10 C.After the reagent has been added (about 30 minutes), the reactionmixture is slowly allowed to heat up to room temperature, is cooledagain to 0 C. and cautiously mixed with 10 parts by volume of acetone.About two-thirds of the solvent are now evaporated under reduced pres.-sure, the residue is poured on to 200 parts of ice and the cold mixtureis acidified with 6 parts by volume of glacial acetic acid. The mixtureis rapidly extracted three times with 100 parts by volume of methylenechloride each time, the extracts are washed with water untilthe reactionis neutral to litmus, dried with sodium sulfate and evaporated in vacuo.The dry residue is dissolved in 13 parts by volume of anhydrous pyridineand mixed with 1.3 parts by volume of freshly distilledbenzoyl chlorideat 5 C. with stirring and the exclusion of moisture The temperature isallowed to rise slowly to room tempera:

ture. After 16 hours the mixture is poured on to 200 parts by volume ofice Water and washed with .-50 p arts by volume of methylene chloride.The mixturevis extracted twice more with parts by volume of methylenechloride each time, the extracts are washed with cold 1- molar sodiumhydrogen carbonate solution, water, dilute hydrochloric acid and againwith water, dried with sodium sulfate and evaporated in vacuo. Theresidue is dissolved in 20 parts by volume of benzene and after a shorttreatment with active charcoal is filtered through a small column ofalumina. The solvent is evaporated and the crude product purified bychromatography over alumina (activity H) yields from the benzene eluatesthe dibenzoate of 115,18-cyclo-semiacetal of d,l-A -1lt?-hydroxy 17hydroxy methyl l8 oxo 3 ethylenedioxy-D-homo-androstadiene, which can bepurified by chromatography.

2.4 parts of this dibenzoate are dissolved in 235 parts by volume ofethyl acetate, cooled to 3.0 C. and a dry current of oxygen containingozone is passed through this solution until about 1.05 molar equivalentsof ozone have been consumed. 14 parts by volume of glacial acetic acidare added and 20 grams of zinc dust are added to the solution inportions while stirring. After one hour the solution is filtered ofifrom the zinc and zinc salts and the ethyl acetate solution is washedwith sodium hydrogen carbonate solution of 5 percent strength and water.After drying the ethyl acetate solution with sodium sulfate, filteringand evaporating under reduced pressure to dryness, the crude reactionproduct is subjected to ring closure by boiling a solution in 450 partsby volume of benzene, mixed with 12 parts by volume of glacial aceticacid and 9 parts by volume of piperidine, for one and one half hours inan atmosphere of nitrogen in an apparatus provided with a waterseparator. After cooling, the solution is washed with water, sodiumhydrogen carbonate and water, dried over sodium sulfate and evaporatedunder reduced pressure. After purification by chromatography there isobtained the 18,21-dibenzoate of 11,3,18-cyclosemiacetal of d,l-A -118,21- dihydroxy-l8,20-dioxo-3-ethylenedioxy-pregnadiene.

1 part of the compound so obtained is dissolved in 50 parts by volume ofpure methanol and, after the addition of a solution of 0.01 part ofpotassium hydroxide in parts by volume of methanol and 1 part of a 2percent palladium-carbon catalyst, the mixture is agitated in anatmosphere of hydrogen until 1 mol of hydrogen has been taken up. Thecatalyst is removed by filtration, washed with methanol, the solution isneutralized by the addition of 0.01 part of glacial acetic acid andconcentrated by evaporation in vacuo. The residue is taken up inchloroform, the chloroform solution is washed with water, dried withsodium sulfate and evaporated to dryness in vacuo. From the residuethere is obtained by crystallization the 18,2l-dibenzoate of thellB-18-cyclosemiacetal of d,l-A -11B,21 dihydroxy 18,20-dioxo-3-ethylenedioxy-pregnene.

1 part of the dibenzoate-ketal is mixed with a solution of 0.2 part ofp-toluene sulfonic acid in 60 parts by volume of acetone, and the wholeis stirred overnight. After the addition of a saturated solution ofsodium chloride and extracting by agitation with chloroform, thechloroform solutions are dried and evaporated, and there is obtainedfrom the residue the 18,21-dibenzoate of the 1119,18-cyclosemiacetal ofd,l-l 8-oxo-corticosterone.

1.2 parts of the dibenzoate are mixed with 190 parts by volume ofmethanol, and then a solution of 1.9 parts of potassium bicarbonate in45 parts by volume of water is added in a current of nitrogen Whilestirring. The reaction solution is allowed to stand in a closed vesselunder reduced pressure for 3 days at 20 C. The solution is concentratedto a considerable extent in vacuo in a current of nitrogen at a bathtemperature of 40 C, and the aqueous residue is extracted with 4portions each of 40 parts by volume of a mixture of chloroform and ether(1 :3). The organic solution is washed with water, dried and evaporated.The resulting d,l-l8-oxo-corticosterone or aldosterone is purified bycrystallization from a mixture of acetone and ether.

Instead of reducing the double bond in the l6-position of the11,8,18-cyc1osemiacetal of d,l-A -11;5',21-dihydroxy-18,20-dioxo 3ethylenedioxy pregnadiene described hereinabove the latter may beconverted as follows:

1 part of the dibenzoate of 115,18-cyclosemiacetal of d,l-A-l1fi,21-dihydroxy 18,20-dioxo-3 ethylenedioxypregnadiene is dissolvedin parts by volume of methanol and treated with a solution of 0.2 partof potassium carbonate in 2 parts by volume of water and with 5 parts byvolume of a hydrogen peroxide solution of 30 percent strength. Thereaction mixture is allowed to stand at 0 C. for 48 hours, 2 parts ofsolid potassium monophosphate are then added and the mixture isconcentrated at a bath temperature of 25 C. until about 20 parts byvolume are left. The residue is mixed with 100 parts by volume of waterand extracted with a total of 200 parts by volume of methylene chloridein 3 portions. The extracts are thoroughly washed with water, dried andevaporated.

The crude, partially saponified product thus obtained is rebenzoylatedwith pyridine and benzoyl chloride with the use of chloroform asdiluent. The resulting dibenzoate of 11,53,18-cyc1osemiacetal of d,l-A-ll;3,21-dihydroxy-I6,17a-oxido-18,20-dioxo 3 ethylenedioxy pregnene isdissolved in 50 parts by volume of cold glacial acetic acid and mixedwith 0.5 part by volume of a 32 percent solution of hydrogen bromide inglacial acetic acid. The mixture is maintained at 15 C. for 30 minutesand then poured into 500 parts by volume of ice-water containing 5 partsof potassium hydroxide. The turbid solution is extracted with a total of500 parts by volume of methylene chloride in 3 portions and the extractsare washed with sodium bicarbonate solution and water, dried andevaporated under reduced pressure in an atmosphere of nitrogen. Theresidue is taken up in 35 parts by volume of ethanol of 95 percentstrength and heated to 50 C. for 5 hours while stirring with 10 parts ofRaney nickel catalyst. The catalyst is filtered off and the filtrateevaporated to dryness. On chromatographic purification over aluminumoxide there is obtained the pure 18,21-dibenzoate of115,18-cyclosemiacetal of d,l- A -11B,17a,21-trihydroxy-3,18,2O-trioxopregnene. The dibenzoate thus obtained may be hydrolized as follows:

1.2 parts of the dibenzoate are mixed with palts by volume of methanol,and then a solution of 1.9 parts of potassium bicarbonate in 45 parts byvolume of water is added in a current of nitrogen While stirring. Thereaction solution is allowed to stand in a closed vessel under reducedpressure for 3 days at 20 C. The solution is concentrated to aconsiderable extent in vacuo in a current of nitrogen at a bathtemperature of 40 C., and the aqueous residue is extracted with 4portions each of 40 parts by volume of a mixture of chloroform and ether(1:3). The organic solution is washed with water, dried and evaporated.The resulting d,l-A -11,8,17a,2l-trihydroxy-3,l8,20-trioxopregnene orits 11B,18-cyclosemiace' tal of the formulae:

CHiOH O=OH CHaOH is purified by recrystallization from a mixture ofacetone and ether. This compound is described in our copending 2. Thelactone of A -11B-hydroxy-17-formy1-D homo-androstadiene-3-one-18-acid.

3. The lactone of A -1lfi-hydroxy-B-ethylenedioxy-17-formyl-D-homo-androstadiene-1S-acid.

liatent application Serial No. 711,164, filed concurrently herewith.

What is claimed is:

1. A member of the group consisting of the lactone of A-1lfl-hydroxy-l7-formy1-D-homo androstadiene 3- 5 0ne-18-acid and theS-ketal with lower alkylene glycol. N0 ces c

1. A MEMBER OF THE GROUP CONSISTING OF THE LACTONE OF$4,16-11B-HYDROXY-17-FORMYL-D-HOMO-ANDROSTADIENE -3ONE-18-ACID AND THE3-KETAL WITH LOWER ALKYLENE GLYCOL.